Elevation of low density lipoprotein cholesterol is treated by bile acid sequestering resins. However, these resins produce transient or permanent elevations of very low density lipoprotein (VLDL) triglyceride. Since hypertriglyceridemia may be a risk factor for coronary heart disease, more information is needed about the effects of chronic bile sequestration on VLDL metabolism. We have observed that resins cause acute elevations of VLDL in all subjects and the rise correlates with pre-existing triglyceride levels. In some, these elevations rapidly regress and pretreatment VLDL levels ensue; in others, prolonged or permanent elevations occur. Since chronic bile sequestration has been documented to cause increased hepatic cholesterol production, increased influx of cholesterol into plasma in VLDL and increased flux of cholesterol through plasma, it seems reasonable that VLDL-triglyceride influx into plasma and turnover is also increased. Therefore, we propose the following two hypotheses: (1) Bile sequestration causes acute and chronic increases of VLDL production in all subjects. (2) In patients with an ability to rapidly increase VLDL clearance, plasma levels return to normal, albeit with increased VLDL turnover; in those unable to readily adapt clearance mechanisms, prolonged or permanent increases in VLDL levels occur. We seek to test these hypotheses by performing paired studies of VLDL-triglyceride turnover in subjects before and after bile sequestration. This will be done in subjects with hypercholesterolemia alone, hypertriglyceridemia alone, and both. If our hypotheses are correct, it will point to the need for inhibiting the increased VLDL flux when resin therapy is used. Bile sequestrants will also become powerful research tools, as they can be used to reliably increase VLDL flux in vivo in man. The effects of this perturbation can then be studied in normals and subjects with dyslipoproteinemias.